Substituted azetibine compounds



-Emilio Testa, Vacalio, Tieino,

United States Patent SUBSTITUTED AZETHDENE CQMPOUNDS Switzerland, and Luigi Fontanella and Giulio Matlii, Milan, Italy, assignors to Lepetit S.p.A., Milan, Etaly No Drawing. Filed Dec. 18, 1959, Set. No. 860,314 Claims priority, application Great Britain Dec. 23, 1958 6 Claims. (Cl. 266-239) This invention is concerned with new pharmacologically active compounds. More particularly, the invention is concerned with pharmacologically active N-alkylazetidines of the formula V wherein R and R represent hydrogen, lower alkyl, cycloalkyl, aryl and aralkyl radicals; and R represents lower their quaternary addition salts.

The compounds of the invention have been found to possess adrenolytic and hypotensive activity. For instance l-ethyl-3-phenylazetidine is active at less than mg./kg.'on subcutaneous administration to rats. A'particular property of the compounds of this class is that of antagonizing not only adrenaline, as it usually occurs with all hypotensive compounds, but also noradrenaline. On the contrary, the quaternary addition salts of the new compounds are active as sympatholytic agents.

The low toxicity of all compounds of the invention al.

lows their administration in therapeutically effective doses. The process of the invention consists in hydrogenating a 3-substituted azetidine of the formula wherein R and R have the above significance, R besides the above significance for R can represent also an alkoxy group, with an excess of lithium aluminum hydride in an anhydrous inert organic solvent, and if desired in converting the formed l-alkyl-azetidine into its quaternary addition salts.

For practical purposes it is preferred to add dropwise a solution of the selected l-acylazetidine in the desired solvent to a suspension of LiAlH in the same solvent. Alternatively, a solution containing a l-unsubstituted azetidine and an equivalent amount of carboxylic acid alkyl ester can be added to the LiAlH suspension. During the addition, the l-acylazetidine is continuously formed and is immediately hydrogenated to the desired l-alkylazetidine in the presence of an hydrogenating agent.

The starting materials are prepared by reacting a 3-substituted azetidine of the formula:

wherein R and R have the above-indicated significance, with the chloride or the anhydride of a carboxylic acid of the formula R COOH, wherein R is as above defined, if desired in the presence of a tertiary aminic base, at a temperature of 0120 C., as described in our copending application Serial No. 860,325, filed simultaneously herewith, now U.S. Patent 3,037,019. The 3-sub- 1 Chem. 614, 158-66 (1958).

The following examples are illustrative of the invention.

Example J.1,3-Diethyl-3-Phenylazetidine To a suspension of 15 g. of lithium aluminum hydride a1 y y y p y or p y y radicals, and with n in 300 ml. of anhydrous diethyl ether a solution of 30 g.

of 3-phenyl-3-ethyl-l-acetylazetidine in 200 ml. of anhydrous diethyl ether is slowly added. Then the mixture is refluxed for 2.5 hours, cooled and mixed with about ml. of a 10 percent ammonium chloride solution. After filtration the ether is evaporated and the residue distilled collecting at 8090 C./0.40.6 mm.. yield 25 g. (89%), B.P, 160 C.

Example 2..],3-Diethyl-3-Phenylazetidine Example 3.],3-Diethyl-3-Phenylazctidine-Methyl Iodide An ether solution of l,S-diethyl-3-phenylazetidine is treated at room temperature with an equimolecular amount (in respect of the azetidine) of methyl iodide. The oily product formed crystallizes with cooling and scraping; it is very hygroscopic. M.P. C. (dec.)

Example 4.-]-Propyl-3-Ethyl-3-Phenylazetidine To a suspension of 15 g. of LiA1H in ml. of anhydrous diethyl other a solution of 50 g. of 3-ethyl-3- phenylazetidine and 36.5 g. of ethyl propionate in 250 ml. of anhydrous diethyl ether is slowly added. The mix ture is refluxed for 3 hours, cooled and mixed with about 25 ml. of a 10 percent ammonium chloride solution. After filtration the ether is separated and the residue is distilled. B.P. 90-95 0.4 mm.; yield 49 g. (85%).

Example 5 .I -Ethyl-3-Phenylazetidine Example 6.-1-Ethyl-3-Phenylazetidine To a suspension of 30 g. of LiAlH in 300 ml. of anhydrous diethyl ether a solution of 82 g. of 3-phenylazetidine and 63 g. of ethyl acetate in 500 ml. of anhydrous diethyl ether is slowly added. The mixture is treated as described in the above Example 5 and gives 75% of l-ethyl- 3-phenylazetidine.

Example 7.1Ethyl-3-Phenylazetidine Methyl Iodide The compound, prepared as described in Example 3, has M.P. 110116 C.

Example 8.1-(2-Br0m0benzyl) -3,3-Dime thylazetidine To a suspension of 15 g. of LiAlI-L, in 200 ml. of diethyl ether a solution of 40 g. of 1-(2-bromobenzoyl)-3,3-dimethylazetidine (prepared from 3,3-dimethylazetidine and 2-bromobenzoyl chloride by conventional processes, B.P. 140-l50 C./0.60.8 mm.) in 300 ml. of diethyl ether is slowly added. The mixture is then treated as described inEXample 1. Yield.86%. B.P.95-97C.

Example 9.1-(2-Br0m0benzyl) -3,3-Dimethylazetidine Methyl Iodide It is prepared according to the process described in EX- ample 3. M.P. 130-140 C.

Examples to According to the process described in Example 1, the following azetidines are prepared. Yields and boiling points are given.

'1-n-butyl-3-ethyl-3-pheny1, Y. 87%, B.P. 90/ 0.2. 1-n-pentyl-3-ethyl-3-phenyl, Y. 75 B.P. 98100/ 0.4. 1-iso-pentyl-3-ethyl-3-phenyl, Y. 84%, B.P. 95 0.2. 1-ter-penty1-3-ethyl-3-phenyl, Y. 88.5%, B.P. 88-90/ 0.3. 1-phenylethyl-3-ethyl-3-phenyl, Y. 60% B.P. 130/ 0.2. 1-phenylpropy1-3-ethyl-3-phenyl, Y. 78.5% B.P. 150/ 0.4.

Examples 16 to 24 According to the process described in Example 2, the following azetidines are prepared.

1-n-propyl-3-ethyl-3-phenyl, Y. 99.5%, B.P. 9095/ 0.4.

Example 25.1-Methyl-3-Phenyl-3-Ethylazetidine It is prepared from 38 g. 1-carbethoxy-3-phenyl-3-ethy1- azetidine according to the process described in Example 1. Yield 25 g. (88%). B.P. -90/0.4 mm.

We claim:

. 1-ethyl-3-phenylazetidine.

. 1-ethyl-3-phenylazetidine methyl iodide.

l,3-diethyl-3-pheny1azetidine. 1-propyl-3-ethyl-3-phenylazetidine.

1- 2-bromobenzyl -3 ,3-dimethylazetidine. 1-(2-bromobenzyl)-3,3-dimethylazetidine methyl io- References Cited in the file of this patent Mannich et al.: Berichte, vol. 70, pages 210, 213 (1937).

Mannich et al.: Berichte, Vol. 72-13, pages 409-505 (1939).

Degering: Organic Nitrogen Compounds, pages 491- 92 (1945). 7

Gaylord: Reduction with Complex Metal Hydrides, Interscience Publishers, Inc., New York, N.Y., 1956, pages 569-578. 

1. 1-ETHYL-3-PHENYLAZETIDINE. 